The long-term goal of this research is to understand the nerual and chemical mechanisms that generate the different states of the brain and organism: waking (W), slow wave sleep (SWS) and paradoxical sleep (PS or rapid eye movement sleep, REM). During these states, the activity of the cerebral cortex undergoes fundamental changes, which are importantly determined by modulatory inputs from the basal forebrain. In human disease, lesions in this area can result in deficits in cortical activation and arousal, yet also in SWS. The aim of the proposed research is to identify by their anatomical features and neurotransmitters, including acetylcholine, GABA and glutamate, those basal forebrain neurons which are responsible for cortical activation that occurs during W and PS, and those which are reciprocally involved in cortical deactivation that occurs during SWS. Moreover, whether basal forebrain neurons, including cholinergic, GABAergic and possibly glutamatergic cells, modulate cortical activity in a rhythmic manner during cortical activation will be tested according to the thesis that such rhythmic modulation may provide a mechanism for integrated coherent activity across cortical regions. In a first series of experiments, neurons will be recorded by extracellular (or intracellular) technique in urethane-anesthetized rats to be characterized according to their discharge (or membrane) properties in relation to the cortical electroencephalogram (EEG) during undisturbed, irregular slow wave EEG and during stimulus- evoked, activated EEG. The electrophysiologically characterized neurons will be labelled with neurobiotin by juxtacellular (or intracellular) technique, revealed as cholinergic, GABAergic or possibly glutamatergic by dual fluorescent staining and delineated according to their somatodendritic morphology and axonal projections. In a subsequent experimental series, basal forebrain neurons will be recorded by extracellular technique in head-restrained animals to be characterized according to their discharge in relation to the EEG during natural states of W, SWS and PS. Again, they will be labelled by juxtacellular technique for subsequent identification as cholinergic, GABAergic or possibly glutamatergic and for delineation of their efferent projections. These studies will for the first time identify the specific neurons that are critically involved in state determination and reveal the discharge/membrane properties, chemical neurotransmitters and efferent projections by which they modulate cerebral activity across the sleep-wake cycle.